ClinVar Genomic variation as it relates to human health

Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23418865)

The p.Leu262ArgfsTer4 variant in SMPD1 (also known as p.Leu260ArgfsTer4 due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 12712061, 15234149, 12369017, 17011332) and has been identified in 0.008% (2/24384) of African chromosomes and 0.001% (1/128550) of European (non-Finnish) chromosomes the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727252). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 195086) as pathogenic by EGL Genetic Diagnostics and as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 262 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in combination with reported pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Leu262ArgfsTer4 variant is pathogenic (VariationID: 93315 198093; PMID: 12712061, 15234149, 12369017, 17011332). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it causes loss of function, its presence in combination with other pathogenic variants in affected individuals, and its low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).

Variant summary: SMPD1 c.785_807del23 (p.Leu262ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249834 control chromosomes. The variant, c.785_807del23, has not, to our knowledge, been reported in the literature in individuals affected with Niemann-Pick Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 195086). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is present in population databases (rs794727252, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Leu262Argfs*4) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801).

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.